Adipose-targeted microneedle patch co-delivering semaglutide and rosiglitazone unlocks adipose browning efficacy for obesity therapy

Abstract Current clinical management of obesity relies primarily on glucagon-like peptide-1 (GLP-1) receptor agonists or peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists. However, GLP-1 agonists often lead to weight regain after discontinuation, while PPAR-γ agonist efficacy is limited by the pro-inflammatory adipose microenvironment. Here, we report an adipose-targeted nanocomposite microneedle patch (LRSG-SG@MN) for obesity treatment via an immuno-metabolic modulation strategy based on the co-delivery of rosiglitazone and semaglutide. This platform leverages the intrinsic affinity of nano-lipid droplets for adipocytes to deliver rosiglitazone, thereby activating PPAR-γ signaling and initiating mitochondrial biogenesis. Concurrently, the sustained release of semaglutide reprograms the local immune microenvironment by driving macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotypes. Mechanistically, this resolution of adipose inflammation alleviates the suppression of thermogenesis, creating a circuit that potentiates the browning effects of rosiglitazone. In high-fat diet-induced obese mice, this strategy demonstrated robust efficacy, significantly reducing adiposity and ameliorating glucolipid metabolic disorders. Notably, the system exhibited excellent weight maintenance capacity following treatment cessation without significant rebound, achieving efficient and durable anti-obesity outcomes. This study unveils the non-central immunomodulatory function of semaglutide and establishes an adipose-targeted, long-acting nanocomposite microneedle platform that achieves combined therapeutic outcomes through adipose tissue inflammatory reprogramming coupled with browning induction, offering a novel strategy for sustainable obesity management.